1. Technical Field
The present invention relates to a method for treating acute and chronic pancreatitis.
2. Background Art
Acute pancreatitis is a common clinical problem which remains evasive of specific therapy (Leach et al., 1992). Each year more than 210,000 admissions to U.S. hospitals are caused by acute pancreatitis while another 150,000 are due to chronic pancreatitis. Pancreatitis is most often caused by alcoholism or biliary tract disease. Less commonly, it is associated with hyperlipemia, hyperparathyroidism, abdominal trauma, vasculitis or uremia. The average length of hospitalization for the acute disease is 12.4 days, with a significant number of patients staying much longer because of associated complications.
Chronic ethanol abuse is the most common cause of acute and chronic pancreatitis in the West, yet the pathophysiology of this disease remains poorly understood (Steinberg and Tenner, 1994). There are few medical therapies or pharmacologic agents currently available which have been shown to decrease the severity, duration, complication rate, or mortality for this common disease. Care for these patients, regardless of the etiology, remains primarily supportive, with attention directed towards maintaining an adequate circulating blood volume, supporting renal and respiratory systems, and providing adequate nutrition. This lack of specific therapy has prompted a great number of prospective trials during the past two decades in hopes of finding some way to decrease the progression and severity of this disease. To date, specific therapy remains unknown and a search for new, more effective modalities is necessary.
The overall mortality for acute pancreatitis varies between 6 and 18% and can raise as high as 50% in the more fulminant form (Steinberg and Tenner, 1994; Imrie and Whyte, 1975; Jacobs et al., 1977). Interestingly, the prognosis for this disease appears more dependent upon its systemic manifestations and complications than upon the severity of the local pancreatic inflammation (Imrie and Whyte, 1975; Jacobs et al., 1977). In fact, as many as 60% of deaths from acute pancreatitis which occur within one week of onset can be attributed to adult respiratory distress syndrome (ARDS), which cannot be distinguished from sepsis-associated ARDS (Steinberg and Tenner, 1994; Jacobs et al., 1977).
Chronic pancreatitis develops in those patients who continue to drink after their first bout of pancreatitis or those with gallstone pancreatitis for unknown reasons. The recurrent bouts of acute pancreatitis subsequently become less severe and less life threatening. The typical patient with chronic pancreatitis, however, is admitted to the hospital approximately one to two times per year for the rest of their lives. These patients have a decreased life span when compared to their peers (Imrie and Whyte, 1975; Steinberg and Tenner, 1994). Despite the less severe course of the disease, it causes chronic debilitating pain and numerous hospitalizations and loss of productivity. These patients often have chronic pain to such a degree that they become dependent upon narcotics or require operative intervention in attempts to remove or oblate some of the chronically inflamed pancreas.
It was noted in 1966 that dogs suffering from an experimental model of severe pancreatitis did not die as frequently if their abdomen was washed with Ringer's lactate to remove the pancreatic associated ascitic fluid (PAAF) (Rodgers and Carey, 1966). It was suggested that peritoneal lavage removed some toxic substance(s) within the PAAF.
During the 1970s and early 1980s, several investigators examined the toxic effect of PAAF on multiple organ systems. Ellison and colleagues conducted a number of experiments in an attempt to determine the factor or factors present in the pancreatic ascites which was responsible for the systemic effects seen during acute pancreatitis. Their studies showed that a substance was present in PAAF which was responsible for the hemoconcentrating effect, as well as hypotension seen during severe attacks (Ellison et al., 1981). They subsequently demonstrated that ARDS could be induced when the lungs of healthy animals were lavaged with small amounts of PAAF. Hepatic mitochondrial respiration and oxygen consumption was diminished in vitro when hepatic cells were exposed to PAAF (Coticchia et al., 1986; Pappas et al., 1978). This toxin, therefore, was not specific for one cell or tissue type; in fact, it has profound effects on all organ systems examined.
This "cytotoxic factor" had not been positively identified, yet several clinical studies by Ranson et al. (1978), and Stone et al. (1980) supported the presence of this group of toxin(s) in humans by showing that peritoneal lavage early in the course of acute pancreatitis could decrease the incidence and severity of systemic sequelae and decrease overall mortality. Recent studies by the applicant has documented the presence of inflammatory cytokines within pancreatic ascites (human and animal) supporting the role of these mediators in the development of systemic complications associated with acute pancreatitis. (Norman et al, 1994a, Norman et al, 1995a,b; co-pending U.S. patent application Ser. Nos. 08/167,698 and 08/369,386).
Over the past decade, a somatostatin analog has undergone several clinical, as well as laboratory trials, in an attempt to show beneficial effects of suppressing pancreatic exocrine function pharmacologically during acute pancreatitis. The majority of investigators have shown beneficial effects only with treatment prior to the onset of pancreatitis, and disappointing results when somatostatin was given after the acute inflammatory process had started (Murayama et al., 1990; Zhu et al., 1991; Spillenaar et al., 1989).
A curious aspect of acute pancreatitis is the systemic response which is seen following inflammation initiated within the pancreas. Acute pulmonary, renal, and hepatic failure, generalized water retention, hypocalcemia, hypoxia, and acid/base disturbances are all common complications of pancreatitis. The mechanism for the involvement of these other organ systems probably involves activation of the cytokine cascade, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor (TNF) in a manner not significantly different from sepsis syndromes (Heath et al., 1993; Larson and Henson, 1983; Deitch, 1992; Michie and Wilmore, 1990; Dinarello et al., 1993). Serum levels of these peptides have been shown to correlate to a high degree with the severity of acute pancreatitis in humans, and can also be demonstrated within pancreatic ascites (Heath et al., 1993; Ellison et al., 1981). Other findings have shown that much of the intrinsic pancreatic damage seen in acute pancreatitis is due to the release of cytokines from macrophages and other white blood cells which migrate into the damaged gland (Steer, 1992; Tani et al., 1987; Van Ooijen et al., 1990; Schoenberg et al., 1992; Kelly et al., 1993; Gross et al., 1993; Guice et al., 1991; Heath et al., 1993; Norman and Franz, 1994b; Norman et al., 1994a; Norman et al., 1995a; Norman et al., 1994c; Norman et al., 1994d; Leach et al., 1992; Dinarello et al., 1993; Grewal et al., 1994a; Grewal et al., 1994b; Cioffi et al., 1993; Lowry, 1993; McKay et al., 1994; Formela et al., 1994; Dolan et al., 1994; Oppenheim et al., 1993).
Recent evidence investigating the pathophysiology of chronic pancreatitis has shown that IL-1 may play an important role in this form of pancreatitis as well (Bamba et al, 1994). These authors followed thirty-three patients with chronic pancreatitis and have found each one to have sustained elevations in serum Interleukin-1. Applicants have found, using immunohistochemistry with similar patients, that IL-1 is indeed present in the chronically inflamed human pancreas whereas it is never found in the normal pancreas. Bamba and his colleagues have subsequently investigated the role of IL-1 in another fifty patients with chronic pancreatitis (Bamba et al, J. Gastroenterology 1996, in press) and has suggested that IL-1 plays a very important role in the maintenance of chronic inflammation within the gland. This chronic inflammation is believed to be the cause of their pain and hospitalization.
Guice et al. (1989) have shown that pancreatitis-associated adult respiratory distress syndrome (ARDS) is to a large degree neutrophil mediated and is not iron-dependent or hydroxyl-radical mediated. They suggested that the process of acute pancreatitis leads to neutrophil recruitment, sequestration, and adherence to alveolar capillary endothelial cells with lung injury ultimately a result of neutrophil-generated products including cytokines. These cytokines are active in low concentrations (picomolar-femtomolar) and are not produced in the normal disease-free state. They may function as mediators in a autocrine, paracrine, and endocrine fashion, and, therefore, may induce inflammation or tissue damage locally, as well as at great distances (Dinarello et al., 1993; Cioffi et al., 1993; Lowry, 1993; Oppenheim et al., 1993).
The administration of IL-1 to rabbits (Wakabayashi et al., 1991; Okusawa et al, 1988; Ohlsson et al., 1990; Aiura et al., 1991) and primates (Fischer et al., 1991) has been shown to result in hypotension, tachycardia, lung edema, renal failure, and, eventually, death, depending on the dose. These signs and symptoms are similar to those demonstrated by patients with severe acute pancreatitis. When the serum from the IL-1 treated animals is examined, the elevation of other cytokines is evident, mimicking the levels seen in acute pancreatitis in humans (Guice et al., 1991; Heath et al., 1993).
Recent investigations have shown that serum levels of inflammatory cytokines correlate to a high degree with the clinical severity of pancreatitis. In a recent publication, Heath et al. (1993) showed significantly higher serum IL-6 levels (approximately 10-fold higher) in patients with severe acute pancreatitis than those with mild acute pancreatitis (Heath et al., 1993). These researchers demonstrated that the clinical course of those patients with higher levels of IL-6 was more complicated and protracted than those with low or undetectable IL-6. A similar study presented at the 1994 meeting of the Pancreatic Society of Great Britain and Ireland showed elevation IL-1, IL-6, and Tumor necrosis factor-.alpha. (TNF-.alpha.) in all patients with severe pancreatitis which correlated very well with systemic symptoms, complications, and mortality (McKay et al., 1994).
IL-1, IL-6, and TNF-.alpha. can be isolated from pancreatic ascites in both humans and experimental animals (Heath, 1993; Norman and Franz, 1994b; McKay et al., 1994; Dolan et al., 1994), and again, levels correlate with the severity of disease. It is interesting to note that the molecular weight of these three cytokines is between 10,000 and 25,000 daltons as suggested by Carey and associates as early as 1983.
Applicant has also shown that TNF-.alpha., IL-1 and IL-6 are rapidly and predictably elevated during acute pancreatitis and that levels are highest within the pancreas itself (Norman et al., 1994a). Applicant suggest that this is evidence of cytokine production within the pancreas which may be partially cleared by the liver.
There seems little doubt now that several inflammatory cytokines are activated and detectable in pathologic concentrations in the serum and ascites of humans, as well as experimental animals, during bouts of acute and chronic pancreatitis.
This complements the large body of evidence currently available which supports the roles of IL-1 and TNF as major mediators of the systemic response to diseases such as sepsis and pancreatitis and as activators of the remaining members of the cytokine cascade (Dinarello et al., 1993). Fischer et al. (1991) demonstrated that the administration of a naturally occurring antagonist to IL-1 will significantly blunt the cytokine cascade and improve survival in baboons given a lethal dose of live bacteria. In this study, IL-1 receptor antagonist (IL-1ra) significantly attenuated the decrease in mean arterial pressure and cardiac output and improved survival over control. The systemic IL-1 and IL-6 responses observed as a result of the bacteremia were diminished significantly, correlating with a decrease in the systemic response to the sepsis.
Studies by Aiura et al. (1991) have shown that IL-1ra is protective in a rabbit model of hypotensive gram-positive septic shock. The administration of IL-1ra in this animal model has been shown to maintain mean arterial pressure compared to control, as well as decreasing lung water and maintaining urine output. This work demonstrated the role of IL-1 and the protective role of IL-1ra in gram-positive shock which was thought to be due to a separate mechanism from gram-negative shock. The common pathway for the systemic manifestations of these two different models of shock has been shown to involve IL-1 as a central mediator. Evidence is mounting for the role of IL-1 as a principal mediator in a patient's clinical response to multiple different stresses regardless of the etiology (including pancreatitis).
Grewal et al. (1994) have shown that treatment with anti-TNF antibody therapy improves survival in an animal model of acute pancreatitis when given prophylactically. Treatment of humans with antibodies (monoclonal or polyclonal) carries significant risks. The antibodies represent a foreign protein which is itself antigenic to the recipient. This has been shown to be a problem in approximately 3-5% of all patients receiving an initial treatment with antibodies (PDR, 1994). However, the incidence of complications, including death from serum sickness, has been shown to increase to as much as 30% with repeat administration. For these reason no current manufacture of antiserum or antibodies allows the repeat administration of these proteins.
An additional theoretical problem with antibody therapy when applied to antagonism of human cytokines is that the affinity of the cytokine for its membrane bound receptor is several orders of magnitude (3 to 5) higher than is the affinity of the proposed blocking antibody for the cytokine in question. The stoichiometry dictates that the cytokine has an increased chance of binding to the receptor than to the corresponding antibody, thereby mediating its detrimental effects. Since cytokines are known to illicit their intra-cellular responses and subsequent detrimental effects when only a single cytokine has found its way to a membrane bound receptor, the importance of complete blockade of the circulating cytokine becomes of paramount importance. (Oppenheim, et al., 1993).
Hence, to be effective on repeated administration, an antibody should not be antigenic. In general, efforts to reduce antigenicity have included forming chimeric molecules that comprise human antibody constant domains fused with murine antibody variable domains humanizing murine antibodies so that all but the six hypervariable loops of the antibody combining site are of human sequence and, most definitively, producing human antibodies in vitro and thus bypassing the need for immunization in other species. However, these procedures are not always available, do not always provide antibody with the necessary avidity and are costly to provide. Therefore, other treatment modalities must be explored.
P U.S. Pat. Nos. 4,522,827 and 4,902,708 disclose methods of treating acute pancreatitis. However, none of these patents take into effect the specific pathology of the disease, thereby proposing treatments which are not specific and are directed to the symptoms only, not the underlying mechanism.
U.S. Pat. No. 5,196,402 discloses the use of S-adenosyl methionine for the use of treatment of pancreatitis in the context of a complication in the graft rejection in pancreas transplant, a very uncommon procedure. The patent does not address acute pancreatitis as a disease in the nontransplant patient. The vast majority of cases of pancreatitis are not associated with pancreatic transplants.
From the above review, it is apparent that systemic complications associated with severe pancreatitis are mediated by pro-inflammatory cytokines. Applicant has previously shown that proximal blockade of the cytokine cascade at the level of the interleukin-1 (IL-1) receptor results in attenuated production of these inflammatory mediators and is associated with a significant decrease in the severity of pancreatitis as set forth in co-pending U.S. patent application Ser. No. 167,698 assigned to the assignees of the present invention and incorporated herein by reference. These changes are associated with a survival advantage, therefore it would be useful to increase the efficacy of proximal cytokine antagonism in order to decrease the mortality of acute and chronic pancreatitis.
Additional treatments are needed which take into account that the local, as well as systemic, effects seen during pancreatitis are due to activation of the cytokine cascade whereby proximal inhibition of this cascade will decrease the severity of the inflammatory process.